This invention relates to the use of nonsteroidal compounds for the production of pharmaceutical agents for treatment of inflammations, selected compounds and production processes thereof.
In addition to a large number of steroid compounds, which bind well to the glucocorticoid receptor and have an antiinflammatory action (glucocorticoids), nonsteroidal compounds are known that namely bind to the glucocorticoid receptor, for which to date no antiinflammatory action has been shown, however [cf. Nature Medicin 4 (1998) 92, Mol. Pharmacol. 52 (1997) 571]. In addition, nonsteroidal compounds were described that are derived from steroidal compounds, have an affinity to the glucocorticoid receptor and probably have an antiinflammatory action that is mediated by the receptor [J. Med. Chem. 36, (1993), 3278-3285]. In animal experiments, however, these compounds did not show any advantages relative to steroidal glucocorticoids, i.e., it was not possible to separate the antiinflammatory action from the metabolic effects, e.g., suppression of the suprarenal function.
From WO 98/54159, nonsteroidal compounds are known that have a high gestagenic activity. In the document, there is the observation that the claimed compounds partially also have action on the glucocorticoid and/or mineral corticoid receptor. In this connection, however, there is neither actual mention of compounds nor disclosure of test results. That is to say that from the pool of generically claimed compounds of WO 98/54159, compounds that are not specified in more detail are known that have both high gestagenic activity and action on the glucocorticoid receptor. In terms of industrial applicability, however, compounds that have a selectivity with respect to the above-mentioned actions are advantageous.
In turn, from WO 00/32584, phenol derivatives that have a dissociation of action between antiinflammatory action and undesirable metabolic side effects are known as nonsteroidal antiinflammatory agents.
The compounds that are disclosed in the prior art are still in need of improvement with respect to their dissociation of action between antiinflammatory action and the undesirable side effects.
The object was therefore to make available new nonsteroidal antiinflammatory agents that show a dissociation of action that is at least as good or better than the compounds of the prior art.
Nonsteroidal compounds have now been found that bind well to the glucocorticoid receptor and, mediated by this bond, produce an antiinflammatory action. In the experiment, these compounds show a significantly better or at least equally good dissociation of action between antiinflammatory and undesirable actions and are superior to the previously described nonsteroidal glucocorticoids or have at least just as good an action.
According to this invention, the following compounds of general formula I that have an antiinflammatory action are suitable for use for the production of pharmaceutical agents: 
in which
R1 and R2 are the same or different and stand for a hydrogen atom, a C1-C5 alkyl group, or, together with the C-atom of the chain, stand for a ring with a total of 3-7 links,
R3 stands for a straight-chain or branched C1-C5 alkyl group or a straight-chain or branched, partially or completely fluorinated C1-C5 alkyl group,
A stands for the group 
xe2x80x83(the dashed line means the interface site), in which
R4 to R8 are the same or different from one another and mean a hydrogen atom, a halogen atom, a cyano group, a nitro group, a COOR9 group
whereby R9 stands for a hydrogen atom, a straight-chain or branched C1-C5 alkyl group or a benzyl group,
a CONR10 group,
whereby R10 stands for a hydrogen atom or a straight-chain or branched C1-C5 alkyl group,
an NHR11 group,
whereby R11 stands for a hydrogen atom, a straight-chain or branched C1-C5 alkyl group, a straight-chain or branched, partially or completely fluorinated C1-C5 alkyl group, a C1-C5 acyl group, an xe2x80x94SO2xe2x80x94(C1-C5) alkyl group or an xe2x80x94SO2-phenyl group that is optionally substituted by halogen or a C1-C5 alkyl group,
a straight-chain or branched C1-C5 alkyl group, a straight-chain or branched C2-C5 alkenyl group, a straight-chain or branched C2-C5 alkinyl group, a straight-chain or branched C1-C5 alkyl group that is partially or completely substituted by fluorine atoms, a C1-C5 acyl group, an aryl radical or a heteroaryl radical,
R4 and R5 together with the two carbon atoms of ring A mean a saturated or unsaturated carbocyclic ring with a total of 5-7 links,
Ar stands for a ring system, selected from the group of general partial formula 1 or 2, 
in which
radicals X3a, X3b, X4, X6, X7 (in partial formula 1) and Y4, Y5, Y7, and Y8 (in partial formula 2) are the same or different and mean a hydrogen atom, a straight-chain or branched C1-C5 alkyl group, or a straight-chain or branched, partially or completely fluorinated C1-C5 alkyl group,
radicals X4, X6, X7 (in partial formula 1) or Y5, Y7, Y8 (in partial formula 2) in addition are the same or different and mean a hydrogen atom, a halogen atom, a hydroxy group, a C1-C5 alkoxy group or a C1-C5 alkanoyloxy group,
as well as their racemates or separately present stereoisomers, and optionally their physiologically compatible salts.
The compounds of general formula I according to the invention can be present as different stereoisomers because of the presence of asymmetry centers. Both the racemates and the separately present stereoisomers are part of the subject matter of this invention.
A special subject of this invention are the isomers that turn the plane of polarized light in the way that they are referred to as (+)-compounds.
The substituents that are defined as groups or radicals in the compounds of general formula I can have the meanings below in each case.
The C1-C5 alkyl groups R1, R2, R3, R4, R5, R12, Xn, and Yo can be straight-chain or branched and can stand for a methyl-, ethyl-, n-propyl-, iso-propyl-, n-butyl, iso-butyl, tert-butyl or n-pentyl, 2,2-dimethylpropyl-, 2-methylbutyl- or 3-methylbutyl group. A methyl group or ethyl group is preferred.
If R1 and R2 together with the C-atom of the chain form a 3- to 7-membered ring, the latter optionally can be substituted by 1-2 oxygen atoms and can be, for example, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl ring.
For a partially or completely fluorinated C1-C5 alkyl group, the partially or completely fluorinated alkyl groups that appear above are considered. Of the latter, the trifluoromethyl group or pentafluoroethyl group, as well as partially fluorinated alkyl groups, for example the 5,5,5,4,4-pentafluoropentyl group or 5,5,5,4,4,3,3-heptafluoropentyl group, are preferred. The trifluoromethyl group and the pentafluoroethyl group are preferred.
The substituents of phenyl ring A, independently of one another, can have the meanings that are defined in the claims, such as a hydrogen atom, a halogen atom, a cyano group, a nitro group, an NHR11 group, whereby R11 stands for a hydrogen atom, a straight-chain or branched C1-C5 alkyl group, a straight-chain or branched, partially or completely fluorinated C1-C5 alkyl group, a C1-C5 acyl group, an xe2x80x94SO2xe2x80x94(C1-C5)alkyl group or an xe2x80x94SO2-phenyl group that is optionally substituted by halogen or a C1-C5 alkyl group, a straight-chain or branched C1-C5 alkyl group, a straight-chain or branched C2-C5 alkenyl group, a straight-chain or branched C2-C5 alkinyl group, a straight-chain or branched C1-C5 alkyl group that is partially or completely substituted by fluorine atoms, a C1-C5 acyl group, an aryl radical or a heteroaryl radical.
Preferred are phenyl rings A, which carry 1-3 non-hydrogen substituents.
In addition, R4 and R5 together with the two carbon atoms of ring A can mean a saturated or unsaturated carbocyclic ring with a total of 5 to 7 links, such as, for example, indane, naphthalene, tetrahydronaphthalene, benzocycloheptane.
A subject of the invention is the use of the compounds of general formula I in which R4 to R8 are the same or different from one another and mean a hydrogen atom, a halogen atom, a cyano group, a nitro group, a COOR9 group, whereby R9 stands for a hydrogen atom, a straight-chain or branched C1-C5 alkyl group or a benzyl group, a CONR10 group, whereby R10 stands for a hydrogen atom or a straight-chain or branched C1-C5 alkyl group, an NHR11 group, whereby R11 stands for a hydrogen atom, a straight-chain or branched C1-C5 alkyl group, a straight-chain or branched, partially or completely fluorinated C1-C5 alkyl group, a C1-C5 acyl group, a xe2x80x94SO2xe2x80x94(C1-C5)alkyl group or an xe2x80x94SO2-phenyl group that is optionally substituted by halogen or a C1-C5 alkyl group, a straight-chain or branched C1-C5 alkyl group, a straight-chain or branched C2-C5 alkenyl group, a straight-chain or branched C2-C5 alkinyl group, a straight-chain or branched C1-C5 alkyl group that is partially or completely substituted by fluorine atoms, a C1-C5 acyl group, an aryl radical or a heteroaryl radical.
The designation halogen atom or halogen means a fluorine, chlorine, bromine or iodine atom. Preferred is a fluorine, chlorine or bromine atom.
For a C2-C5 alkenyl group, for example, a vinyl, 2-substituted vinyl group, 1-propenyl, 2-propenyl, 2- or 3-substituted 2-propenyl group, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, and 3-methyl-1-butenyl group are considered. Preferred are the alkenyl groups, which carry the double bond in 1- or 2-position. As substituents for the vinyl group or the propenyl group, primarily the methyl group or the ethyl group is suitable.
A C2-C5 alkinyl group is defined as, for example, an ethinyl, 1-propinyl, 2-propinyl, 1-butinyl, 2-butinyl, 3-methyl-1-butinyl, 4-methyl-1-butinyl or 1-pentinyl group. Preferred are the alkinyl groups that carry a triple bond in 1-position or 2-position.
With the C1-C5 acyl group, for example, a formyl, acetyl, propionyl, n-butyroyl, 2-methylpropionyl, n-valeroyl, 2-methylbutyroyl, 3-methylbutyroyl or a pivaloyl group is meant.
With a sulfonyl(C1-C5) alkyl group R11, for example, a methylsulfonyl group or an ethylsulfonyl group is meant.
For the sulfonylphenyl group R11 that is optionally substituted by halogen or a C1-C5 alkyl group, 2-chloro(phenylsulfonyl), 3-chloro(phenylsulfonyl), 4-chloro(phenylsulfonyl), 2-methyl(phenylsulfonyl), 3-methyl(phenylsulfonyl), and 4-methyl(phenylsulfonyl) can be mentioned. The sulfonyl group is bonded with its free valency to the nitrogen atom of the NHR11 group.
Aryl means a phenyl group or a substituted phenyl group.
As substituents of the aryl group, halogen atoms, the cyano, nitro, C1-C5 alkoxy, amino, hydroxy, carboxy and C1-C5 alkanoyl groups, branched and unbranched C1-C5 alkyl groups, branched and unbranched C1-C5 alkyl groups, which can be partially or completely fluorinated, are suitable.
Heteroaryl comprises aromatic heterocyclic 5- and 6-rings, which can contain in the ring 1-3 additional heteroatoms from the group of oxygen, nitrogen or sulfur. Preferred are heterocyclic five-membered rings. In particular, furyl, thienyl, pyridyl, thiazolyl, oxazolyl, oxadiazolyl, and imidazolyl can be mentioned.
The heteroaryl groups optionally can be substituted by branched and unbranched C1-C5 alkyl groups, branched and unbranched C1-C5 alkyl groups that can be fluorinated and/or halogen atoms.
The hydroxy groups that are possible for radicals Xn, Yo can optionally be defined below as ethers or esters:
As a C1-C5 alkyl group for etherification of hydroxy groups, the above-mentioned alkyl groups are suitable, especially a methyl group or ethyl group.
As a C1-C5 alkanoyl group for esterification of hydroxy groups, a formyl, acetyl, propionyl, butyryl, iso-butyryl, valeryl or iso-valeryl or pivaloyl group is considered, preferably an acetyl group.
As a C1-C5 acyl group for esterification of hydroxy groups, for example, the above-mentioned alkanoyl groups, preferably in turn an acetyl group, or a benzoyl, toluoyl, phenylacetyl, acryloyl, cinnamoyl or cyclohexylcarbonyl group, can be mentioned.
As a C1-C5 alkanoyloxy group for X4, X6, X7, Y4, Y5, Y7 or Y8, a formyloxy, acetoxy, propionyloxy, butyryloxy, iso-butyryloxy, valeryloxy or iso-valeryloxy group is considered, preferably an acetoxy group.
Preferred are compounds in which Ar stands for partial formula 2, and Y4 means a methyl group.
Especially preferred are compounds in which Ar stands for partial formula 2, Y4 means a methyl group, and the other substituents Y5, Y7 and Y8 mean hydrogen.
Nonsteroidal compounds as such with a mixed profile that consists of gestagenic and androgenic activity in different manifestations are already the subject of WO 98/54159. The compounds of general formula I according to claim 1 that are to be used according to this patent application for the production of pharmaceutical agents with antiinflammatory action fall within the scope of the general formula that is contained in WO 98/54159, but are not preferred as a group or directly disclosed as compounds there. They are thus novel and also meet the patenting requirement of inventive activity because of the antiinflammatory action that was found and that is dissociated from undesirable metabolic effects or other effects.
Undesirable actions/effects in the context of this invention are metabolic actions or else bonds to other steroid receptors.
The compounds of general formula I cited by name below fall namely within the scope of the general formula that is cited in WO 98/54159 but are not previously described by name there. They are thus novel and also meet the patenting requirement of inventive activity because of the antiinflammatory action that was found and that is dissociated from undesirable side effects.
These compounds as such therefore also belong to the subject matter of this invention and are listed below.
Their naming is to be illustrated in the following example: 
6-[4-(2-Chloro-3-R5-4-R6-5-R7-6-R8-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
The following compounds are the subject of this invention:
5-[4-(5-Fluoro-2-methylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide
6-[4-(2-chloro-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
5-[4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide
6-[4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
5-[4-(3-fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-phthalide
6-[4-(3-fluoro-4-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2-bromo-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(indan-4xe2x80x2-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92) 6-[4-(indan-4xe2x80x2-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(+) 6-[4-(indan-4xe2x80x2-yl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(5-fluoro-2-vinylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92) 6-[4-(5-fluoro-2-vinylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(+) 6-[4-(5-fluoro-2-vinylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(4-trifluoromethyphenyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92) 6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(4-trifluoromethylphenyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one
(+) 6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(4-trifluoromethylphenyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2-bromo-3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92) 6-[4-(2-bromo-3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(+) 6-[4-(2-bromo-3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92) 6-[4-(3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(+) 6-[4-(3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2-cyano-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2-ethenyl-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2-ethyl-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(5-fluoro-2-phenylphenyl-2-hydroxy-4-methy-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-{5-fluoro-2-(furan-2xe2x80x2-yl)phenyl}-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2-bromo-3,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(1-naphthyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92) 6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(1-naphthyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one
(+) 6-[2-hydroxy-4-methyl-2-trifluoromethyl-4-(1-naphthyl)-valeroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[4-(2-chloro-3-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2-chloro-3-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2-chloro-3-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[4-(2-chloro-4-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2-chloro-4-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2-chloro-4-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[4-(2-chloro-6-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2-chloro-6-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2-chloro-6-fluoro-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[4-(2,3-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2,3-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2,3-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[4-(2,4-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2,4-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2,4-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[4-(2,5-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2,5-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroy]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2,5-dichlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[4-(4-bromo-2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroy]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(4-bromo-2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(4-bromo-2-chlorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[4-(2-chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2-chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2-chloro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[4-(2-chloro-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2-chloro-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2-chloro-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[4-(2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylhexanoylamino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylhexanoylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2,4-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2,4-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2,4-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2,5-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2,3,5-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2,3,5-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2,3,5-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2,3,4-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2,3,4-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2,3,4-trifluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(3-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(3-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(3-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(4-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(4-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(4-chloro-2-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2-fluoro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92) 6-[4-(2-fluoro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one
(+) 6-[4-(2-fluoro-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2-bromophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[4-(4-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(4-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(4-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[4-(5-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(5-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(5-fluoro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[4-(5-chloro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(5-chloro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(5-chloro-2-trifluoromethyl-phenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2-chlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92) 6-[3-{1-(2-chlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+) 6-[3-{1-(2-chlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2-chlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(2-chlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(2-chlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methy-2,3-benzoxazin-1-one
6-[3-{1-(2-chlorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(2-chlorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(2-chlorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2-chloro-4-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(2-chloro-4-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(2-chloro-4-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2-chloro-4-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(2-chloro-4-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(2-chloro-4-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2-chloro-5-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(2-chloro-5-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(2-chloro-5-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2-chloro-5-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(2-chloro-5-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(2-chloro-5-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethyl-propionyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2,4-dichlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(2,4-dichlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(2,4-dichlorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2,4-dichlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(2,4-dichlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(2,4-dichlorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2-trifluoromethyl-phenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92) 6-[3-{1-(2-trifluoromethyl-phenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+) 6-[3-{1-(2-trifluoromethyl-phenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclopropyl}-2-hydroxy-2-trifluromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(5-fluoro-2-trifluoromethyl-phenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl]-amino-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(2-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(2-fluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(2-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(2-fluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2-fluorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(2-fluorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(2-fluorophenyl)-cyclopentyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2-fluorophenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(2-fluorophenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(2-fluorophenyl)-cyclohexyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2,3-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(2,3-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(2,3-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl-amino]-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2,3-difluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92) 6-[3-{1-(2,3-difluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(+) 6-[3-{1-(2,3-difluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2,5-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(2,5-difluorophenyl)-cyanopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(2,5-difluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2,3,5-trifluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(2,3,5-trifluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(2,3,5-trifluorophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionyl-amino]-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2,3,5-trifluorophenyl)-cyclobuty}1-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(2,3,5-trifluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(2,3,5-trifluorophenyl)-cyclobutyl}-2-hydroxy-2-trifluoromethylpropionyl-amino]-4-methyl-2,3-benzoxazin-1-one
6-[3-{1-(2-bromophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[3-{1-(2-bromophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[3-{1-(2-bromophenyl)-cyclopropyl}-2-hydroxy-2-trifluoromethylpropionylamino]-4-methyl-2,3-benzoxazin-1-one
6-[2-hydroxy-4-methyl-4-(3-methyl-2-nitrophenyl)-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92) 6-[2-hydroxy-4-methyl-4-(3-methyl-2-nitrophenyl)-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
(+) 6-[2-hydroxy-4-methyl-4-(3-methyl-2-nitrophenyl)-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide
(xe2x88x92) 5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide
(+) 5-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-phthalide
6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroyl-amino]-4-methyl-2,3-benzoxazin-1-one
(+) 6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92) 6-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one
(+) 6-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one
5-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide
(xe2x88x92) 5-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide
(+) 5-[4-(2-acetylamino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide
5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide
(xe2x88x92) 5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide
(+) 5-[4-(5-fluoro-2-mesylaminophenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-phthalide
6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92) 6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one
(+) 6-[4-(2-bromo-3-methoxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92) 6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one
(+) 6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92)-6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one
(+)-6-[4-(2-bromo-3-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeroylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92) 6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one
(+) 6-[4-(2,3-difluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one
6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92) 6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one
(+) 6-[4-(2,6-difluorophenyl)-2-hydroxy-4-methyl-4-trifluoromethylcaproylamino]-4-methyl-2,3-benzoxazin-1-one
6-{3-[4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one
(xe2x88x92) 6-{3-[4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one
(+) 6-{3-[4-(2-chloro-5-fluorophenyl)-tetrahydropyran-4-yl]-2-hydroxy-2-trifluoromethylpropionylamino}-4-methyl-2,3-benzoxazin-1-one
A special aspect of this invention are the above-indicated 2,3-benzoxazin-1-ones.
Another aspect of this invention are the above-indicated compounds, whose 2,3-benzoxazin-1-one in 3-position carries a methyl group.
If the compounds of general formula I are present as salts, this can be, for example, in the form of hydrochloride, sulfate, nitrate, phosphate, pivalate, maleate, fumarate, tartrate, benzoate, mesylate, citrate or succinate.
If the compounds according to the invention are present as racemic mixtures, they can be separated into the pure, optically active forms according to the methods of racemate separation that are familiar to one skilled in the art. For example, the racemic mixtures can be separated into the pure isomers by chromatography on an even optically active carrier material (CHIRALPAK AD(R)). It is also possible to esterify the free hydroxy group in a racemic compound of general formula I with an optically active acid and to separate the diastereoisomer esters that are obtained by fractionated crystallization or by chromatography and to saponify the separated esters in each case to form the optically pure isomers. As an optically active acid, for example, mandelic acid, camphorsulfonic acid or tartaric acid can be used.
Process for the Production of the Compounds According to the Invention
The compounds according to the invention can be obtained by the chain C(R1)(R2)xe2x80x94CH2xe2x80x94C(OH)(R3)xe2x80x94Bxe2x80x94NHxe2x80x94Ar being built up starting from a commercially available phenyl compound or a phenyl compound that is available according to known methods, whereby radical R3 is introduced in the last step or the ring system of formulas (1) or (2) (xe2x95x90Ar) is introduced with the formation of the amide bond Bxe2x80x94NHxe2x80x94Ar.
Compounds that were produced according to one of the processes below and in which A is a substituted aromatic ring, optionally can be substituted selectively at this aromatic radical according to known processes. Examples of this process are the catalytic hydrogenation of multiple bonds, the nitration and the halogenation. Halogen and nitro substitutions offer, moreover, possible further modifications. Thus, for example, aryl bromides can be reacted with boron, tin or zinc reagents under palladium catalysis in the way that is known to one skilled in the art. Nitro compounds can be reduced to aniline derivatives, for example hydrogenolytically, or with metals, such as, e.g., iron or zinc. The aniline derivatives can be further reacted after diazotization in a known way, for example in terms of Sandmeyer reactions.
(A)
An xcex1-ketocarboxylic acid of general formula II 
in which A, R1 and R2 have the meanings that are indicated in formula I,
is either optionally esterified with a compound of general formula
(R12)3SiR3xe2x80x83xe2x80x83(III)
in which R3 has the meaning that is indicated in general formula I, and R12 means a C1-C5 alkyl group,
in the presence of a catalyst, or is reacted with an alkyl metal compound, for example a Grignard reagent or a lithium alkyl, to form a compound of formula IV 
As catalyst, fluoride salts or basic compounds, such as alkali carbonates, are suitable (J. Am. Chem. Soc. 111, 393 (1989)).
The ester is optionally cleaved again and then reacted with a compound of general formula V
Arxe2x80x94NHxe2x80x94R13xe2x80x83xe2x80x83, (V)
whereby R13 means a hydrogen atom or a C1-C5 acyl group, and Ar has the meaning that is indicated in general formula I,
whereby then radical R13 is cleaved off to obtain a compound of formula I or is reacted directly with a compound of general formula
Arxe2x80x94NHxe2x80x94R13xe2x80x83xe2x80x83(V)
whereby R13 means a hydrogen atom or a C1-C5 acyl group, and Ar has the meaning that is indicated in general formula I, optionally after activation of the acid function by, e.g., conversion into the acid chloride, whereby then radical R13 is cleaved off in any sequence and is reacted with a compound of general formula III
(R12)3xe2x80x94SiR3xe2x80x83xe2x80x83(III)
in which R3 and R12 have the above-indicated meanings, to obtain a compound of formula I.
(B)
A compound of general formula VI 
in which A, B, R1, R2, and R3 have the meaning that is indicated in formula I and LG means any leaving group, is reacted with a compound of general formula V
Arxe2x80x94NHxe2x80x94R13xe2x80x83xe2x80x83(V)
whereby R13 means a hydrogen atom or a C1-C5 acyl group, and Ar has the meaning that is indicated in general formula I, whereby then radical R13 is cleaved off to obtain a compound of formula I.
In this case, the compound of general formula VI can optionally also be formed only as intermediate product, which can be isolated, if desired, or else can be produced only in situ, e.g., this can be an acid chloride that is formed intermediately from a corresponding carboxylic acid. As leaving groups, in this respect, for example, a fluorine, chlorine or bromine atom, or, if no intermediate acid chloride is formed, the mesylate radical or tosylate radical, can be mentioned.
The binding of substances to the glucocorticoid receptor (GR) is examined with the aid of a recombinantly produced receptor. Cytosol preparations of Sf9 cells, which had been infected with recombinant baculoviruses, which code for the GR, are used for the binding studies. In comparison to the reference substance [3H]-dexamethasone, the substances show a high to very high affinity to the GR.
In addition, these compounds in the mineral corticoid receptor (MR)-binding test with use of cytosol preparations that consist of Sf9 cells, which had been infected with baculoviruses that code for the MR, and with use of [3H]-aldosterone as a reference substance, show affinities to the MR.
As an essential molecular mechanism for the antiinflammatory action of glucocorticoids, the GR-mediated inhibition of the transcription of cytokines, adhesion molecules, enzymes and other pro-inflammatory factors can be seen. This inhibition is produced by an interaction of the GR with other transcription factors, e.g., AP-1 and NF-kappa-B (for a survey, see Cato, A. C. B. and Wade, E., BioEssays 18, 371-378, 1996).
The compounds of general formula I according to the invention inhibit the secretion of the cytokine IL-8 that is triggered by lipopolysaccharide (LPS) in human monocyte cell line THP-1. The concentration of the cytokines was determined in the supernatant with use of commercially available ELISA kits.
The antiinflammatory actions of the compounds of general formula I were tested in the animal experiment by testing in the croton oil-induced inflammation in rats and mice (J. Exp. Med. (1995), 182, 99-108). In this connection, croton oil in ethanolic solution was administered topically to the animals"" ears. The test substances were also administered topically or systemically simultaneously with or two hours before the croton oil. After 16-24 hours, the ear weight was measured as a yardstick of the inflammatory edema, the peroxidase activity was measured as a yardstick of the invasions of granuloctyes, and the elastase activity was measured as a yardstick of the invasions of neutrophilic granuloctyes. In this test, the compounds of general formula I inhibit the three above-mentioned inflammation parameters both after topical administration and after systemic administration.
One of the most frequent undesirable effects of a glucocorticoid therapy is the so-called xe2x80x9csteroid diabetesxe2x80x9d [cf. Hatz, H. J., Glucocorticoide: Immunologische Grundlagen, Pharmakologie und Therapierichtlinien [Glucocorticoids: Immunological Bases, Pharmacology and Therapy Guidelines], Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998]. The reason for this is the stimulation of the gluconeogenesis in the liver by induction of the enzymes that are responsible for this effect and by free amino acids, which develop from the degradation of proteins (catabolic action of glucocorticoids). A key enzyme of the catabolic metabolism in the liver is the tyrosinamino transferase (TAT). The activity of this enzyme can be determined photometrically from liver homogenates and represents a good yardstick of the undesirable metabolic actions of the glucocorticoids. To measure the TAT induction, the animals are sacrificed 8 hours after the test substances are administered, the livers are removed, and the TAT activity in the homogenate is measured. In this test, at doses at which they have an antiinflammatory action, the compounds of general formula I induce little or no tyrosinamino transferase.
In summary, the new compounds of general formula I compared to the previously used steroidal glucocorticoids have the following advantages:
nonsteroidal structure (i.e., the substances are also effective in patients who, because of an allergic reaction to the steroid basic structures of conventional glucocorticoids, can no longer access the latter for therapy (cf. Lutz, M E, el-Azhary R A, Mayo Clin. Proc. 72, 1141-1144, 1997).
good antiinflammatory action with little metabolic action
Because of their antiinflammatory and additional antiallergic, immunosuppressive and antiproliferative actions, the compounds of general formula I according to the invention can be used as medications for treatment or prophylaxis of the following pathologic conditions in mammals and humans: In this case, the term xe2x80x9cDISEASExe2x80x9d stands for the following indications:
(i) Lung diseases, which coincide with inflammatory, allergic and/or proliferative processes:
Chronically obstructive lung diseases of any origin, mainly bronchial asthma
bronchitis of different origins
all forms of restrictive lung diseases, mainly allergic alveolitis,
all forms of pulmonary edema, mainly toxic pulmonary edema
sarcoidoses and granulomatoses, especially Boeck""s disease
(ii) Rheumatic diseases/auto-immune diseases/degenerative joint diseases, which coincide with inflammatory, allergic and/or proliferative processes:
All forms of rheumatic diseases, especially rheumatoid arthritis, acute rheumatic fever, polymyalgia rheumatica,
reactive arthritis
inflammatory soft-tissue diseases of other origins
arthritic symptoms in degenerative joint diseases (arthroses)
traumatic arthritides
collagen diseases of other origins, e.g., systemic lupus erythematodes, scleroderma, polymyositis, dermatomyositis, Sjxc3x6gren""s syndrome, Still syndrome, Felty""s syndrome
(iii) Allergies, which coincide with inflammatory and/or proliferative processes:
All forms of allergic reactions, e.g., Quincke""s edema, hay fever, insect bites, allergic reactions to pharmaceutical agents, blood derivatives, contrast media, etc., anaphylactic shock, urticaria, contact dermatitis
(iv) Vascular diseases (vasculitis)
Panarteritis nodosa, temporal arteritis, erythema nodosum
(v) Dermatological diseases, which coincide with inflammatory, allergic and/or proliferative processes:
Atopic dermatitis (mainly in children)
psoriasis
pityriasis rubra pilaris
erythematous diseases, triggered by different noxae, e.g., radiation, chemicals, burns, etc.
bullous dermatoses
diseases of the lichenoid group
itching (e.g., of allergic origins)
seborrheal eczema
rosacea
pemphigus vulgaris
erythema exudativum multiforme
balanitis
vulvitis
hair loss, such as alopecia areata
cutaneous T-cell lymphoma
(vi) Nephropathies, which coincide with inflammatory, allergic and/or proliferative processes:
Nephrotic syndrome
all nephritides
(vii) Liver diseases, which coincide with inflammatory, allergic and/or proliferative processes:
Acute liver cell decomposition
acute hepatitis of different origins, e.g., virally-, toxically- or pharmaceutical agent-induced
chronically aggressive and/or chronically intermittent hepatitis
(viii) Gastrointestinal diseases, which coincide with inflammatory, allergic and/or proliferative processes:
Regional enteritis (Crohn""s disease)
ulcerative colitis
gastritis
reflux esophagitis
gastroenteritides of other origins, e.g., native sprue
(ix) Proctological diseases, which coincide with inflammatory, allergic and/or proliferative processes:
Anal eczema
fissures
hemorrhoids
idiopathic proctitis
(x) Eye diseases, which coincide with inflammatory, allergic and/or proliferative processes:
Allergic keratitis, uveitis, iritis
conjunctivitis
blepharitis
optic neuritis
chorioiditis
sympathetic ophthalmia
(xi) Diseases of the ear-nose-throat area, which coincide with inflammatory, allergic and/or proliferative processes:
Allergic rhinitis, hay fever
otitis externa e.g., caused by contact dermatitis, infection, etc.
otitis media
(xii) Neurological diseases, which coincide with inflammatory, allergic and/or proliferative processes:
Cerebral edema, mainly tumor-induced cerebral edema
multiple sclerosis
acute encephalomyelitis
meningitis
different forms of convulsions, e.g., infantile nodding spasms
(xiii) Blood diseases, which coincide with inflammatory, allergic and/or proliferative processes:
Acquired hemolytic anemia
idiopathic thrombocytopenia
(xiv) Tumor diseases, which coincide with inflammatory, allergic and/or proliferative processes:
Acute lymphatic leukemia
malignant lymphoma
lymphogranulomatoses
lymphosarcoma
extensive metastases, mainly in breast, bronchial and prostate cancers
(xv) Endocrine diseases, which coincide with inflammatory, allergic and/or proliferative processes:
Endocrine orbitopathy
thyrotoxic crisis
de Quervain""s thyroiditis
Hashimoto""s thyroiditis
hyperthyroidism
(xvi) Organ and tissue transplants, graft-versus-host disease
(xvii) Severe shock conditions, e.g., anaphylactic shock, systemic inflammatory response syndrome (SIRS)
(xviii) Substitution therapy, with:
Innate primary suprarenal insufficiency, e.g., congenital adrenogenital syndrome
acquired primary suprarenal insufficiency, e.g., Addison""s disease, autoimmune adrenalitis, meta-infective, tumors, metastases, etc.
innate secondary suprarenal insufficiency, e.g., congenital hypopituitarism
acquired secondary suprarenal insufficiency, e.g., meta-infective, tumors, etc.
(xix) vomiting, which coincides with inflammatory, allergic and/or proliferative processes:
e.g., in combination with a 5-HT3-antagonist in cytostatic-agent-induced vomiting
(xx) Pain with inflammatory origins, e.g., lumbago.
The compounds of general formula I according to the invention can also be used for therapy and prophylaxis of additional pathologic conditions that are not mentioned above, for which synthetic glucocorticoids are now used (see in this connection Hatz, H. J., Glucocorticoide: Immunologische Grundlagen, Pharmakologie und Therapierichtlinien, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1998).
All previously mentioned indications (i) to (xx) are described in detail in Hatz, H. J., Glucocorticoide: Immunologische Grundlagen, Pharmakologie und Therapierichtlinien, Wissenschaftliche Verlagesgesellschaft mbH, Stuttgart, 1998.
For the therapeutic actions in the above-mentioned pathologic conditions, the suitable dose is different and it depends on, for example, the active strength of the compound of general formula I, the host, the type of administration and the type and severity of the conditions that are to be treated, as well as the use as prophylactic agent or therapeutic agent.
In addition, the invention provides
(i) The use of a compound of the invention according to formula I or its mixture for the production of a medication for treating a DISEASE;
(ii) a process for treating a DISEASE, and said process comprises an administration of an amount of compound according to the invention, whereby the amount suppresses the disease and whereby the amount of compound is given to a patient who requires such a medication;
(iii) a pharmaceutical composition for treating a DISEASE, and said treatment comprises one of the compounds according to the invention or its mixture and at least one pharmaceutical adjuvant and/or vehicle.
In general, satisfactory results are to be expected in animals when the daily doses comprise a range of 1 xcexcg to 100,000 xcexcg of the compound according to the invention per kg of body weight. In larger mammals, for example humans, a recommended daily dose lies in the range of 1 xcexcg to 100,000 xcexcg per kg of body weight. Preferred is a dose of 10 to 30,000 xcexcg per kg of body weight, more preferably a dose of 10 to 10,000 xcexcg per kg of body weight. For example, this dose is suitably administered several times daily. For treating acute shock (e.g., anaphylactic shock), individual doses can be given that lie considerably above the above-mentioned doses.
The formulation of the pharmaceutical preparations based on the new compounds is carried out in a way that is known in the art, by the active ingredient being processed with the vehicles, fillers, substances that influence decomposition, binding agents, humectants, lubricants, absorbents, diluents, flavoring correctives, staining agents, etc. that are commonly used in galenicals and converted into the desired form of administration. In this case, reference is to be made to Remington""s Pharmaceutical Science, 15th Ed. Mack Publishing Company, East Pennsylvania (1980).
For oral administration, especially tablets, coated tablets, capsules, pills, powders, granulates, lozenges, suspensions, emulsions or solutions are suitable.
For parenteral administration, injection and infusion preparations are possible.
For intra-articular injection, correspondingly prepared crystal suspensions can be used.
For intramuscular injection, aqueous and oily injection solutions or suspensions and corresponding depot preparations can be used.
For rectal administration, the new compounds can be used in the form of suppositories, capsules, solutions (e.g., in the form of enemas) and ointments, both for systemic and for local therapy.
For pulmonary administration of the new compounds, the latter can be used in the form of aerosols and inhalants.
For local application to eyes, outer ear channels, middle ears, nasal cavities, and paranasal sinuses, the new compounds can be used as drops, ointments and tinctures in corresponding pharmaceutical preparations.
For topical application, formulations in gels, ointments, fatty ointments, creams, pastes, powders, milk and tinctures are possible. The dosage of the compounds of general formula I should be 0.01%-20% in these preparations to achieve an adequate pharmacological action.
The invention also comprises the compounds of general formula I according to the invention as therapeutic active ingredients. In addition, the compounds of general formula I according to the invention are part of the invention as therapeutic active ingredients together with pharmaceutically compatible and acceptable adjuvants and vehicles. The invention also comprises a pharmaceutical composition that contains one of the pharmaceutically active compounds according to the invention or mixture thereof and a pharmaceutically compatible salt or pharmaceutically compatible adjuvant and vehicle.
The examples below are used for a more detailed explanation of the invention without intending that it be limited to these examples. The syntheses of important precursors, which are not disclosed within the scope of the experimental part, are already prior art and can be deduced in the example from WO 98/54159.
Experimental Part